Abnormalities in mitochondrial function relate to the spectrum of pathological changes seen in Alzheimer's disease. Here we review the causes and consequences of mitochondrial disturbances in Alzheimer's disease as well as how this information might impact on therapeutic approaches to this disease.

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Although hypoxia tolerance in heterothermic mammals is well established, it is unclear whether the adaptive significance stems from hypoxia or other cellular challenge associated with euthermy, hibernation, or arousal. In the present study, blood gases, hemoglobin O 2 saturation (SO2), and indexes of cellular and physiological stress were measured during hibernation and euthermy and after arousal thermogenesis. Results show that arterial O 2 tension (PaO 2 ) and SO2 are severely diminished during arousal and that hypoxia-inducible factor (HIF)-1␣ accumulates in brain. Despite evidence of hypoxia, neither cellular nor oxidative stress, as indicated by inducible nitric oxide synthase (iNOS) levels and oxidative modification of biomolecules, was observed during late arousal from hibernation. Compared with rats, hibernating Arctic ground squirrels (Spermophilus parryii) are well oxygenated with no evidence of cellular stress, inflammatory response, neuronal pathology, or oxidative modification following the period of high metabolic demand necessary for arousal. In contrast, euthermic Arctic ground squirrels experience mild, chronic hypoxia with low SO 2 and accumulation of HIF-1␣ and iNOS and demonstrate the greatest degree of cellular stress in brain. These results suggest that Arctic ground squirrels experience and tolerate endogenous hypoxia during euthermy and arousal.torpor; ischemia; stroke; Spermophilus parryii; reperfusion; inflammation; oxidative stress HIBERNATION IS A UNIQUE PHYSIOLOGICAL STATE of prolonged periods of low body temperature, metabolism, blood flow, and other physiological processes that are disrupted by brief periodic arousal episodes when animals rewarm and reperfuse metabolically active tissues (7). During arousal thermogenesis, blood flow returns to brain and other organs in a reperfusionlike manner at a time of maximal oxygen demand (42, 58). Preservation of neuronal and other cellular morphology during low cerebral blood flow demonstrates that hibernating mammals tolerate pronounced fluctuations in blood flow (16,61). Physiological and cellular stress experienced during euthermy, hibernation, and arousal is less well characterized.Arterial oxygen tension (Pa O 2 ) and tissue lactate measurements show that hibernating ground squirrels are well oxygenated (16,20), sometimes exceeding values in the euthermic state (15). In contrast, oxygen supply may become limiting during arousal thermogenesis. Increases in brain tissue lactate levels during peak oxygen consumption during arousal from hibernation in bats suggest these animals experience oxygen deficiency during arousal and reperfusion (30). However, because tissue lactate was not reported for euthermic bats, it is unclear how brain tissue hypoxia experienced during arousal compares to the euthermic state. Moreover, Pa O 2 was not measured to address the relationship between blood and tissue oxygenation during euthermy, hibernation, and arousal. To characterize physiological challenges associated with arousal thermogenesis, we evaluated b...

Torpor during hibernation defines the nadir of mammalian metabolism where whole animal rates of metabolism are decreased to as low as 2% of basal metabolic rate. This capacity to decrease profoundly the metabolic demand of organs and tissues has the potential to translate into novel therapies for the treatment of ischemia associated with stroke, cardiac arrest or trauma where delivery of oxygen and nutrients fails to meet demand. If metabolic demand could be arrested in a regulated way, cell and tissue injury could be attenuated. Metabolic suppression achieved during hibernation is regulated, in part, by the central nervous system through indirect and possibly direct means. In this study, we review recent evidence for mechanisms of central nervous system control of torpor in hibernating rodents including evidence of a permissive, hibernation protein complex, a role for A1 adenosine receptors, mu opiate receptors, glutamate and thyrotropin-releasing hormone. Central sites for regulation of torpor include the hippocampus, hypothalamus and nuclei of the autonomic nervous system. In addition, we discuss evidence that hibernation phenotypes can be translated to non-hibernating species by H 2 S and 3-iodothyronamine with the caveat that the hypothermia, bradycardia, and metabolic suppression induced by these compounds may or may not be identical to mechanisms employed in true hibernation. Keywords metabolic arrest; metabolic suppression; suspended animationHibernating animals display a variety of adaptations that protect the central nervous system from metabolic challenges and trauma that are injurious in non-hibernating species. These adaptations include profound decreases in brain and body temperature (T b ) and immune function, enhanced antioxidant defenses, and metabolic suppression Zhou et al. 2001; Ross et al. 2006). Metabolic suppression, a regulated and reversible reduction in cellular and tissue need for oxygen and nutrients, matches metabolic demand with supply and is one of the most novel yet least well-understood neuroprotective aspects of hibernation. Knowledge of mechanisms used by hibernating animals to decrease metabolic demand to as low as 2% of basal metabolic rate or 0.01 mL O 2 /g/h

Torpor in hibernating mammals defines the nadir in mammalian metabolic demand and body temperature that accommodates seasonal periods of reduced energy availability. The mechanism of metabolic suppression during torpor onset is unknown although the central nervous system (CNS) is a key regulator of torpor. Seasonal hibernators such as the arctic ground squirrel (AGS) display torpor only during the winter, hibernation season. The seasonal character of hibernation thus provides a clue to its regulation. In the present study we delivered adenosine receptor agonists and antagonists into the lateral ventricle of AGS at different times of the year while monitoring the rate of O2 consumption and core body temperature as indicators of torpor. The A1 antagonist, cyclopentyltheophylline (CPT) reversed spontaneous entrance into torpor. The adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA) induced torpor in 6 out of 6 AGS tested during the mid-hibernation season, 2 out of 6 AGS tested early in the hibernation season and none of the 6 AGS tested during the summer, off-season. CHA-induced torpor within the hibernation season was specific to A1AR activation; the A3AR agonist 2-Cl-IB MECA failed to induce torpor and the A2aR antagonist MSX-3, failed to reverse spontaneous onset of torpor. CHA-induced torpor was similar to spontaneous entrance into torpor. These results show that metabolic suppression during torpor onset is regulated within the CNS via A1AR activation and requires a seasonal switch in the sensitivity of purinergic signaling.

During hibernation in Arctic ground squirrels (Spermophilus parryii), O(2) consumption and plasma leukocyte counts decrease by >90%, whereas plasma concentrations of the antioxidant ascorbate increase fourfold. During rewarming, O(2) consumption increases profoundly and plasma ascorbate and leukocyte counts return to normal. Here we investigated the dynamic interrelationships among these changes. Plasma ascorbate and uric acid (urate) concentrations were determined by HPLC from blood samples collected at approximately 15-min intervals via arterial catheter; leukocyte count and hematocrit were also determined. Body temperature, O(2) consumption, and electromyographic activity were recorded continuously. Ascorbate, urate, and glutathione contents in body and brain samples were determined during hibernation and after arousal. During rewarming, the maximum rate of plasma ascorbate decrease occurred at the time of peak O(2) consumption and peak plasma urate production. The ascorbate decrease did not correlate with mouth or abdominal temperature; uptake into leukocytes could account for only a small percentage. By contrast, liver and spleen ascorbate levels increased significantly after arousal, which could more than account for ascorbate clearance from plasma. Brain ascorbate levels remained constant. These data suggest that elevated concentrations of ascorbate [(Asc)] in plasma [(Asc)(p)] provide an antioxidant source that is redistributed to tissues during the metabolic stress that accompanies arousal.

Many vertebrates are challenged by either chronic or acute episodes of low oxygen availability in their natural environments. Brain function is especially vulnerable to the effects of hypoxia and can be irreversibly impaired by even brief periods of low oxygen supply. This review describes recent research on physiological mechanisms that have evolved in certain vertebrate species to cope with brain hypoxia. Four model systems are considered: freshwater turtles that can survive for months trapped in frozen-over lakes, arctic ground squirrels that respire at extremely low rates during winter hibernation, seals and whales that undertake breath-hold dives lasting minutes to hours, and naked mole-rats that live in crowded burrows completely underground for their entire lives. These species exhibit remarkable specializations of brain physiology that adapt them for acute or chronic episodes of hypoxia. These specializations may be reactive in nature, involving modifications to the catastrophic sequelae of oxygen deprivation that occur in non-tolerant species, or preparatory in nature, preventing the activation of those sequelae altogether. Better understanding of the mechanisms used by these hypoxiatolerant vertebrates will increase appreciation of how nervous systems are adapted for life in specific ecological niches as well as inform advances in therapy for neurological conditions such as stroke and epilepsy.KEY WORDS: Arctic ground squirrel, Cetacean, Hypoxia, Naked mole-rat, Seal, Turtle IntroductionEnvironmental conditions vary enormously for vertebrates, both with respect to the extreme conditions tolerated by a given species at different times and with respect to average living conditions tolerated by different species. Temperature is perhaps the most obvious example: from the poles to the equator, average ambient temperatures vary widely and have been accompanied by physiological adaptations appropriate to resident species; seasonal variations in temperature and resource variability can induce dramatic changes in physiological and/or behavioral patterns including migration and hibernation. Oxygen levels also vary widely, with animals adapted to sea level, high-altitude, underground and aquatic habitats. Oxygen levels can also change dramatically on a shorter-term basis, as can occur in tidal pools or in breath-hold divers. Approximately 20% of the oxygen consumed by the human body is used by the brain. The greater part of this oxygen is used to produce the ATP required to maintain the membrane potentials necessary for electrical signaling with synaptic and action potentials (Harris et al., 2012). In many vertebrates, including adult humans, interruption of the oxygen supply to the brain for more than a few minutes leads to irreversible neurological damage, including neuronal death. Without oxidative phosphorylation, ATP-dependent neuronal processes including ion transport and neurotransmitter reuptake decline sharply. Without pumping, ion gradients fail and neurons depolarize, releasing excessive levels...

Background and Purpose-Hetereothermic mammals tolerate hypoxia during euthermy and torpor, and evidence suggests this tolerance may extend beyond hypoxia to cerebral ischemia. During hibernation, CA1 hippocampal neurons endure extreme fluctuations in cerebral blood flow during transitions into and out of torpor as well as reductions in cerebral blood flow during torpor. In vitro studies likewise show evidence of ischemia tolerance in hippocampal slices harvested from euthermic ground squirrels; however, no studies have investigated tolerance in a clinically relevant model of in vivo global cerebral ischemia. The purpose of the present study was to test the hypothesis that the euthermic Arctic ground squirrel (AGS; Spermophillus parryii) is resistant to injury from asphyxial cardiac arrest (CA). Methods-Estrous-matched female rats were used as a positive control. Female euthermic AGS and rats were subjected to 8-minute CA. At the end of 7 days of reperfusion, AGS and rats were fixed for histopathological assessment. Results-In rats subjected to CA, the number of ischemic neurons was significantly higher (PϽ0.001) compared with control rats in hippocampus and striatum. Cortex was mildly injured. Surprisingly, neuronal counts in AGS were not significantly different in CA and control groups in these brain regions. Conclusion-These data demonstrate that AGS are remarkably tolerant to global cerebral ischemia during euthermia. A better understanding of the mechanisms by which AGS tolerate severe reductions in blood flow during euthermia may provide novel neuroprotective strategies that may translate into significant improvements in human patient outcomes after CA. (Stroke. 2006;37:1261-1265.)